Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders.

Autor: Zhao S; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Zhang Y; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China., Hallgrimsdottir S; Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden., Zuo Y; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Li X; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Batkovskyte D; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Liu S; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Lindelöf H; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Wang S; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China., Hammarsjö A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Yang Y; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China., Ye Y; Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China., Wang L; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China., Yan Z; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Lin J; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Yu C; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Chen Z; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China., Niu Y; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Wang H; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Zhao Z; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.; Baylor Genetics, Houston, TX, 77021, USA., Qiu G; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA., Wu Z; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.; Departments of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, 77030, USA.; Texas Children's Hospital, Houston, TX, 77030, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA., Micule I; Clinic of Medical Genetics and Prenatal Diagnostics, Children's Clinical University Hospital, Vienibas gatve 45, Riga, LV-1004, Latvia., Anderlid BM; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Voss U; Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden., Sulander D; Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden., Kuchinskaya E; Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden., Nordgren A; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden., Nilsson O; Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.; School of Medical Sciences, Örebro University and Department of Pediatrics, Örebro University Hospital, Örebro, Sweden., Zhang TJ; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. jgzhang_pumch@yahoo.com.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China. jgzhang_pumch@yahoo.com.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China. jgzhang_pumch@yahoo.com., Grigelioniene G; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. giedre.grigelioniene@ki.se.; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. giedre.grigelioniene@ki.se., Wu N; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China. dr.wunan@pumch.cn.; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China. dr.wunan@pumch.cn.; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China. dr.wunan@pumch.cn.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. dr.wunan@pumch.cn.
Jazyk: angličtina
Zdroj: NPJ genomic medicine [NPJ Genom Med] 2022 Feb 15; Vol. 7 (1), pp. 11. Date of Electronic Publication: 2022 Feb 15.
DOI: 10.1038/s41525-021-00273-x
Abstrakt: Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.
(© 2022. The Author(s).)
Databáze: MEDLINE
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